In previous work we created congenic strains carrying the DBA/2IBG (D2) region for alcohol preference on chromosome 2, on an otherwise C57BL/6IBG (B6) background. Recently, we have done the construction and testing of interval specific congenic recombinant strains (ISCRS) for the purpose of narrowing the QTL interval. The completion of the draft of sequences of the human genome and the current sequencing project of the mouse genome provides us with long-awaited information. One important impact of the genomic sequences is on the strategy for positional cloning of disease genes. The completion of the genome sequence brings us several major advantages that we can use in positional cloning. First, all of the coding sequences of a chromosomal region of interest can be identified. Secondly, information on the introns, 5'and 3'region of the sequences will be available. Therefore, the gene can be analyzed thoroughly throughout the coding region and the regulatory region. Thirdly, with the availability of all the sequences of a chromosomal region, nucleotide organization, gene ordering, gene expression patterns, and chromosomal structure can be analyzed. At the same time, research resources and genetic data have been accumulated. High throughput technologies for mutation analysis and gene profiling have also developed rapidly to meet the new needs. All of these developments will greatly improve our search for candidate genes in positional cloning. This proposal is to identify gene/s responsible for the QTL of alcohol preference drinking using an integrative strategy. The strategy takes advantage of resources of mouse genome, genome polymorphism, recombinant inbred lines, chemical generated mutations, and high throughput technologies. PUBLIC HEALTH RELEVANCE: We propose to identify gene(s) underlying the major genetic locus regulating alcohol preference drinking, using a strategy that integrates genomic, bioinformatic, and mouse resources, with high throughput technologies We anticipate that the through this study we will further understand the genetic factors that influence alcoholism, which will eventually lead to improved methods of identifying individuals at risk for alcoholism and could enhance methods of prevention and treatment of this major societal problem.